What to Know About Melphalan Flufenamide (Melflufen)

A potential new treatment for multiple myeloma

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Melflufen (melphalan flufenamide) is a new drug being investigated in the treatment of relapsed or refractory multiple myeloma (RRMM). It is a derivative of the chemotherapy drug melphalan. Melflufen is a peptide-drug conjugate; a combination of melphalan and a peptide (small protein) bonded together. Melflufen is given by intravenous infusion (into the vein).

The drug was submitted as a new drug application to the U.S. Food and Drug Administration (FDA) in July 2020. The FDA granted the application priority review and a decision is expected in late February 2021. Melflufen is not yet widely available because it has not been licensed and approved for use in myeloma. However, patients may be treated with the drug as part of a clinical trial.

Drip infusion of a patient in a hospital room

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What Is Multiple Myeloma?

Multiple myeloma is a type of rare, incurable cancer of the blood, also known as hematologic cancer. It affects cells called plasma cells, which are types of white blood cells. There is no cure for multiple myeloma, and it almost always returns, at which point you are said to have “relapsed or refractory” disease.

How Does Melflufen Work? 

As new combinations of anti-myeloma drugs are introduced in earlier lines of therapy, people with RRMM often have disease that is resistant to multiple drugs. Therefore, drugs with novel mechanisms of action are urgently needed.

Melflufen, when combined with the steroid dexamethasone, has the potential to fill this unmet medical need by providing:

  • A novel mechanism of action
  • Clinically meaningful efficacy
  • Manageable safety

Melflufen kills myeloma cells through the use of peptidases (enzymes that break down peptides) which are often found in higher numbers in myeloma cells than in healthy cells. When melflufen enters myeloma cells, the peptidases within the cell break the bond holding the melphalan and the peptidase together. This releases active melphalan within the myeloma cell. The melphalan then causes irreversible DNA damage, leading to cell death.

What the Research Says

Research is ongoing to find new treatments for multiple myeloma and work out ways to improve the use of existing ones.

To help with research, you may be asked to take part in a clinical trial during your treatment.

Melflufen is currently being investigated as a treatment for RRMM patients in clinical trial settings. The clinical trials which have investigated the efficacy of melflufen include:

The O-12-M1 Study

O-12-M1 was an international, multicenter, phase I/II study to establish the dose of melflufen in combination with dexamethasone and investigate the treatment response in patients with RRMM, who were refractory (resistant) to the last line of therapy.

In the O-12-M1 study, a group of 45 patients who had received at least two prior therapies were enrolled between July 2013 and December 2016. The trial sought to discover the maximum tolerated dose of melflufen. The established maximum tolerated dose was 40 mg of melflufen in combination with dexamethasone.

The highest dose cohort tested (55 mg) exceeded the maximum tolerated dose because four of six patients experienced severe adverse effects including neutropenia (low white blood cells) and thrombocytopenia (low platelet count); therefore, the planned highest dose of 70 mg was not tested.

For the trial patients, treatment with melflufen and dexamethasone led to disease stabilization in 76% of the patients.

The median time to next treatment—the start of treatment until the next treatment (or to the patient’s death, whichever happened first)—was 7.9 months. Patients lived for a median of 20.7 months.

HORIZON Clinical Trial

In the phase II HORIZON clinical trial —which took place in 20 locations throughout the United States and Europe—melflufen and dexamethasone were given to a total of 154 patients who had received an average of five previous treatment lines.

All the patients had previously been treated with an immunomodulatory drug and proteasome inhibitor, and they were resistant to pomalidomide and/or daratumumab.

About three in every 10 patients (29%) responded to the treatment, and the average time before myeloma started to come back was four months. These results indicated that melflufen may be beneficial for patients who have had multiple lines of treatment previously.

Adverse events (AEs) led to melflufen dose reductions in 27% of patients and dose delays in 61% of patients. The most common AE leading to dose reduction was thrombocytopenia (low platelet count) which occurred in 14% of patients.

Serious AEs occurred in 49% of patients overall; most commonly reported were pneumonia (9%) and neutropenia (5%). Second primary malignancies occurred in five patients; of these, four had malignancies with cutaneous manifestations. Overall, 10 patients (6%) died from treatment related side effects.


Melflufen is given by intravenous infusion (into the vein). In clinical trials, the dose has been:

  • 40mg of melflufen on the first day of each treatment cycle

40 mg dexamethasone (reduced dose for patients 75 years or older) on days 1, 8, 15, and 22 of each 28-day cycle

In some trials, the dose was reduced in those who experienced an adverse reaction.

Side Effects

The most commonly observed side effects of melflufen include:

• Low blood cell counts—neutropenia and thrombocytopenia 

• Anaemia 

• Fatigue 

• Infections, including pneumonia and upper respiratory tract infections 

• Nausea and diarrhea

Because melflufen is a relatively new drug, new side effects may emerge that have not yet been reported.


As research is ongoing, it's difficult to assess the risks of taking melflufen for RRMM. As patients recruited to clinical trials have often exhausted previous treatments, the chances of adverse effects or even death during and after treatment is possible.

Infections are a major cause of morbidity and mortality in patients with RRMM, due to a depleted immune system. It's important to regularly monitor yourself for signs of infection and report any concerns to your physician as soon as possible.

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8 Sources
Verywell Health uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.
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